Variant classification summary

NM_000044.4:c.94G>A

AR · NP_000035.2:p.(Glu32Lys) · NM_000044.4

GRCh37: chrX:66765082 G>A · GRCh38: chrX:67545240 G>A

Gene: AR Transcript: NM_000044.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

AR

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Glu32Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000044.4:c.94G>A (p.Glu32Lys) in AR is a missense variant absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.

2

Multiple computational predictors suggest no deleterious effect: BayesDel score is 0.079 (low/near-neutral) and SpliceAI predicts no splice impact (max delta 0.01), meeting BP4 at supporting strength.

3

The variant has been reported in somatic cancers (COSMIC COSV65955976, n = 8) but has no ClinVar entry, no published germline disease association, and no functional characterization.

4

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield insufficient evidence in either direction. This variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000044.4:c.94G>A is a missense variant (p.Glu32Lys); it does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No known pathogenic variant resulting in the same amino acid change (p.Glu32Lys) via a different nucleotide substitution has been identified in ClinVar or the published literature.	clinvar
PS2	N/A	No de novo testing with confirmed parentage has been performed or reported for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a deleterious effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control studies have demonstrated a statistically significant increased prevalence of this variant in affected individuals compared to controls. The variant is absent from ClinVar and has no reported clinical observations.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a recognized ACMG/AMP 2015 criterion code. No equivalent criterion applies.
PM1	Not met	Variant lies in exon 1 of AR (NTD/AF1 transactivation domain, residue 32). This position is not within a statistically significant mutational hotspot per cancerhotspots.org, and no ClinVar hotspot cluster has been established for this residue.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Applied at supporting strength per generic ACMG/AMP guidelines for absence from large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No known pathogenic missense variant at the same amino acid residue (Glu32) has been identified in ClinVar to serve as a PM5 comparator.	pm5_candidates
PM6	N/A	No de novo observation has been reported for this variant, with or without confirmed parentage.
PP1	N/A	No family segregation data are available for cosegregation analysis.
PP2	Not assessed	Insufficient data on gene-level missense constraint to determine whether AR has a low rate of benign missense variation. No gnomAD missense Z-score or comparable constraint metric is available in the evidence packet for this X-linked gene.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect: BayesDel score is 0.079 (low, near neutral), and SpliceAI predicts no splice impact (max delta score 0.01). REVEL score is unavailable.	bayesdel spliceai
PP4	N/A	No patient phenotype or clinical data are available to assess whether the proband's features are specific for an AR-related disorder.
PP5	Not met	No reputable source (ClinVar, published literature) has reported this variant as pathogenic. The variant is entirely absent from ClinVar.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Its allele frequency is 0%, which does not exceed the BA1 threshold (>1%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Its allele frequency is 0%, which does not exceed the BS1 threshold (>0.3%).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	This variant has not been observed in a healthy adult individual in a setting where full penetrance would be expected at an early age. The variant is absent from all population databases.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant.
BS4	N/A	No family segregation data are available to assess nonsegregation with disease.
BP1	Not met	AR-related disorders (androgen insensitivity syndrome) are caused by both missense and truncating variants; the disease mechanism is not one in which primarily truncating variants cause disease. BP1 does not apply to genes where missense variants are a well-established pathogenic mechanism.	pvs1_gene_context
BP2	N/A	No phase data are available; the variant has not been observed in trans with a pathogenic variant or in cis with a known pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious effect: BayesDel score is 0.079 (low, near neutral range) and SpliceAI predicts no splicing impact (max delta score 0.01). REVEL is unavailable for this variant. The combined in silico evidence supports a benign interpretation.	bayesdel spliceai
BP5	N/A	No clinical data are available to determine whether an alternate molecular basis for disease has been identified in a proband carrying this variant.
BP6	Not met	No reputable source (ClinVar, published literature) has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (c.94G>A, p.Glu32Lys), not a synonymous variant. BP7 applies only to silent variants with no predicted splice impact.

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